Cyclopenteno-3-carboxyl-4-quinolone derivatives and their bacteriostatic compositions

ABSTRACT

New cyclopenteno-quinolone derivatives of the formula ##SPC1## 
     Wherein 
     R is a saturated or unsaturated aliphatic hydrocarbyl, e.g., alkyl and alkenyl, 
     X is hydrogen or alkyl, and 
     Y is halogen, azido, alkylthio, alkyl-sulfonyl, or nitrile or unsubstituted or substituted (e.g., alkyl mono or di-substituted) amino; 
     And the pharmacologically compatible salts thereof; are outstandingly effective as bacteriostats in mammals.

This is a division of application Ser. No. 515,790, filed Oct. 17, 1974.

The present invention is concerned with new cyclopenteno-quinolonederivatives and therapeutic compositions and uses thereof.

The new cyclopenteno-quinolone derivatives according to the presentinvention are compounds of the general formula: ##SPC2##

Wherein

R is a saturated or unsaturated aliphatic hydrocarbyl, e.g. alkyl andalkenyl,

X is hydrogen or alkyl, and

Y is halogen, azido, alkylthio, alkyl-sulfonyl, or nitrile orunsubstituted or substituted (e.g. alkyl mono or di-substituted) amino;

And the pharmacologically compatible salts thereof.

The amino group Y in the above-given general formula (I) can be not onlya free amino group but also a mono- or dialklamino, mono- ordiacylamino, mono- or dialkylamino-methyleneamino, pyrrolidino orpiperidino radical.

The aliphatic radicals R and the alkyl radicals X and Y can contain upto 5 and preferably up to 3 carbon atoms.

The new compounds according to the present invention differ from thestructurally similar compounds described in German Pat. No. 1,770,951 byhaving a substituent in the cyclopentene ring.

Suprisingly, the new compounds according to the present invention, incomparison with the known compounds, have about the same anti-microbialaction in vitro but a substantially stronger action in vivo, especiallyin the urinary tract.

The new compounds according to the present invention can be prepared,for example, by reacting a compound of the general formula: ##SPC3##

Wherein R and X have the same meanings as above, with a conventionalhalogenation agent, whereafter in the halogen compound thus obtained, ifdesired, the halogen atom is exchanged in conventional manner by anothersubstituent Y and/or converted into a pharmacologically compatible salt.

The starting materials of general formula (II) are described in GermanPat. No. 2,222,833 and can be prepared by the processes describedtherein.

The halogenation reaction according to the present invention can becarried out in conventional manner, preferably with the use ofconcentrated hydrohalic acids, for example concentrated hydrochloricacid in the presence of a zinc salt, for example zinc chloride. Thehalogen compound formed can then be converted by known processes into anazido group, for example with sodium azide in a solvent such as dimethylsulphoxide, into an alkylthio radical, for example by reaction with analkyl mercaptide in dimethyl sulphoxide, into an alkylsulphonyl radical,such as a methylsulphonyl radical, for example by reaction with sodiumsulphinate in dimethyl sulphoxide, or into a nitrile group, for exampleby reaction with sodium cyanide or potassium cyanide. The azido groupcan be converted in known manner into an amino group, for example bycatalytic reduction, which can then, if desired, be alkylated, acylated,condensed with aldehydes to give Schiff bases or reacted to giveamidines. Alkylthio radicals can be oxidized in known manner to give thecorresponding sulphoxides or sulphones, for example with aqueoushydrogen peroxide solution or with m-chloroperbenzoic acid.

Apart from the compounds set out in the following examples, thefollowing compounds are also preferred according to the presentinvention: 1-ethyl-3-carboxy-1,4-dihydro-7-methylamino-cyclopenteno-[1,2-h] quinol-4-one;1-ethyl-3-carboxy-1,4-dihydro-7-dimethylamino-cyclopenteno-[1,2-h]quinol-4-one; 1-ethyl-3-carboxy-1,4-dihydro-7-piperidino-cyclopenteno[1,2-h] quinol-4-one;1-ethyl-3-carboxy-1,4-dihydro-7-(dimethylaminomethyleneamino)-cyclopenteno[1,2-h] quinol-4-one; and1-ethyl-3-carboxy-1,4-dihydro-7-cyanocyclopenteno [1,2-h] quinol-4-one.

The conversion of the compounds of general formula (I), in which X is ahydrogen atom, into pharmacologically compatible salts can be carriedout in conventional manner, for example by neutralization with anon-toxic inorganic base or with a non-toxic amino. Compounds of generalformula (I) in which Y is an amino group can be neutralizedcorrespondingly with non-toxic inorganic or organic acids.

The following Examples are given for the purpose of illustrating,without limitation, the present invention:

EXAMPLE 1 Preparation of1-Ethyl-3-carboxy-7-chloro-1,4-dihydrocyclopenteno [1,2-h] quinol-4-one

5.2 g. 1-ethyl-3-carboxy-1,4-dihydro-7-hydroxycyclopenteno [1,2-h]quinol-4-one were stirred at ambient temperature for 3 hours in amixture of 10.4 ml. concentrated hydrochloric acid and 8.2 g. anhydrouszinc chloride. The reaction mixture was poured into ice water and theresultant precipitate was filtered off with suction and stirred threetimes with 40 ml. amounts of methylene chloride. The combined methylenechloride phases were dried and evaporated to dryness. There wereobtained 3.1 g1-ethyl-3-carboxy-7-chloro-1,4-dihydrocyclopenteno-[1,2-h] quinol-4-onewhich had a melting point of 244°-248° C.

EXAMPLE 2 Preparation of1-Ethyl-7-azido-3-carboxy-1,4-dihydrocyclopenteno [1,2-h] quinol-4-one

2.82 g. sodium azide were stirred for 20 minutes at 200° C. in 14 ml.dimethyl sulphoxide, whereby the greater part of the sodium azidedissolved. The solution was subsequently cooled to 65° C. and then 2.82g. 1-ethyl-3-carboxy-7-chloro-1,4-dihydrocyclopenteno [1,2-h]quinol-4-one were immediately introduced therein spatula-wise so thatthe sodium azide did not precipitate out again, whereafter the reactionmixture was further stirred for 1 hour at 60°-65° C. Subsequently, 68ml. water were added thereto and the reaction mixture was cooled andfiltered with suction. There were obtained 2.8 g. crude1-ethyl-7-azido-3-carboxy-1,4-dihydro-cyclopenteno [1,2-h] quinol-4-one,which was recrystallized from about 20 ml. dimethyl formamide. The yieldwas then 2.05 g. and the product melted at 221°-222° C.

EXAMPLE 3 Preparation of1-Ethyl-7-amino-3-carboxy-1,4-dihydro-cyclopenteno [1,2-h] quinol-4-one

0.54 g. 1-ethyl-7-azido-3-carboxy-1,4-dihydro-cyclopenteno [1,2-h]quinol-4-one were dissolved in 1.7 ml. water and 1.09 ml. 2N aqueoussodium hydroxide solution and hydrogenated with hydrogen in the presenceof Raney nickel at normal temperature and pressure. The reaction mixturewas then purified twice with active charcoal, acidified with glacialacetic acid to pH 4-5 and evaporated. The residue was taken up in alittle water and the finely crystalline undissolved product wasseparated off by centrifuging. It was thereafter slurried with waterthree times and decanted off. Finally, there were obtained 0.12 g.1-ethyl-7-amino-3-carboxy-1,4-dihydro-cyclopenteno [1,2-h] quinol-4-one,which decomposed at 246°-250° C.

EXAMPLE 4 Preparation of1-Ethyl-7-acetylamino-3-carboxy-1,4-dihydro-cyclopenteno [1,2]quinol-4-one

0.5 g. 1-ethyl-7-amino-3-carboxy-1,4-dihydro-cyclopenteno [1,2-h]quinol-4-one were heated under reflux for 20 hours with 10 ml. aceticanhydride. After cooling, the reaction mixture was evaporated and theevaporation residue (0.55 g.) boiled for a few minutes with dimethylformamide. There were obtained 0.25 g.1-ethyl-7-acetylamino-3-carboxy-1,4-dihydro-cyclpenteno [1,2-h]quinol-4-one, which decomposed at 292°-303° C.

The same compound was also obtained when the solution acidified withglacial acetic acid in Example 3 was not worked up immediately but wasleft to stand for a comparatively long time (for example 3 weeks) atambient temperature and then worked up in a manner analogous to thatdescribed in Example 3.

EXAMPLE 5 Preparation of1-Ethyl-3-carboxy-1,4-dihydro-7-methylsulphonyl-cyclopenteno [1,2-h]quinol-4-one

1.45 g. 1-ethyl-3-carboxy-7-chloro-1,4-dihydrocyclopenteno [1,2-h]quinol-4-one were dissolved in 25 ml. dimethyl sulphoxide and 2.55 g.sodium methyl sulphinate were added thereto portionwise at ambienttemperature over the course of 30 minutes. The reaction mixture wasfurther stirred for 3 hours at ambient temperature, subsequently pouredinto 300 ml. water, left to stand for some time at about 5° C. and thenfiltered off with suction. There was obtained 1.4 g.1-ethyl-3-carboxy-1,4-dihydro-7-methyl-sulphonyl-cyclopenteno [1,2-h]quinol-4-one, which decomposed at 238°-240° C.

EXAMPLE 6 Preparation of1-Ethyl-3-carboxy-1,4-dihydro-7-methylthio-cyclopenteno [1,2-h]quinol-4-one

100 mg. 1-ethyl-3-carboxy-7-chloro-1,4-dihydrocyclopenteno [1,2-h]quinol-4-one were dissolved in 1.5 ml. dimethyl sulphoxide and 240 mg.sodium methyl mercaptide were added portionwise at ambient temperaturewithin the course of 5 minutes. The reaction mixture was further stirredfor 2 hours at ambient temperature and the product then precipitated outwith semi-concentrated hydrochloric acid. There were obtained 35 mg.1-ethyl-3-carboxy-1,4-dihydro-7-methylthio-cyclopenteno [1,2-h]quinol-4-one, which had a melting point of 106°-112° C.

The present invention also provides pharmaceutical, particularlybacteriostatic, compositions containing at least one of the newcompounds of general formula (I) and/or at least one pharmacologicallycompatible salt thereof, in admixture with a solid or liquidpharmaceutical diluent or carrier.

The bacteriostatic activity of the instant compounds was measured bydetermining the absolute bacteriostatic minimum concentration against anumber of representative species (see Table 1) and by measuring theexcretion of the test compounds in urine and the bacteriostaticeffectiveness of the urine after oral administration to rats (see Table2).

The results are set out in the following Tables.

                                      TABLE 1                                     __________________________________________________________________________    Absolute Bacteriostatic Minimum Concentrations in μg/ml                    Test Substance                  BACTERIUM GROUP                                                               Staphylococcus                                                                        Escherichia                                                                          Proteus                                              [Prep. Ex. No.]                                                                         aureus (103)                                                                          coli (108)                                                                           mirabilis (298)                1-Ethyl-3-carboxy-7-azido-1,4-dihydro-                                        cyclopenteno[1,2-h]-quinolone (4)                                                                   [2]       4       0.25   0.25                           1-Ethyl-3-carboxy-7-chloro-1,4-dihydro-                                       cyclopenteno[1,2-h]-quinolone (4)                                                                   [1]       32      1      2                              1-Ethyl-3-carboxy-1,4-dihydro-7-methyl-                                       sulfonyl-cyclopenteno[1,2-h]-quinolone-                                                             [5]       8       1      1                              (4)                                                                           Nalidixic acid (Nogram-Winthrop)                                                                              32      1      2                              __________________________________________________________________________

                                      TABLE 2                                     __________________________________________________________________________    BACTERIOSTATIC ACTIVITY OF THE URINE OF RATS                                  FOLLOWING ORAL ADMINISTRATION                                                 Bacteriostatic maximum dilution of urine against Escherichia coli             (106) determined in 50 ml (75 ml) urine samples 22 hours after                20 mg test compound per kg body weight had been orally adminis-               tered. 6 (9) rats were employed for each experiment and every                 value recorded in the Table represents the results of each ex-                periment.                                                                     Test Compound       Prep. Ex. No.                                                                          Max. Dilution                                    __________________________________________________________________________    1-Ethyl-3-carboxy-7-azido-1,4-                                                dihydro-cyclopenteno[1,2-h]-                                                  quinolone-(4)       [2]      1:1440                                           1-Ethyl-3-carboxy-7-chloro-1,4-                                               dihydro-cyclopenteno[1,2-h]-                                                  quinolone-(4)       [1]      1:1200                                           1-Ethyl-3-carboxy-1,4-dihydro-7-                                              methylsulfonyl-cyclopenteno[1,2-h]-                                           quinolone-(4)       [5]      1:413                                            Nalidixic acid (Nogram-Winthrop)                                                                           1:234                                            __________________________________________________________________________

The compounds of general formula (I) can be administered inpharmaceutical compositions enterally and parenterally in solution,suspension or in solid form by admixture with a solid or liquidpharmaceutical diluent or carrier. Enteral and parenteral forms ofadministration can be of any conventional type, for example tablets,capsules, dragees, syrups, solutions, suspensions, drops, suppositoriesand the like. For this purpose, the active material is mixed with asolid or liquid carrier material and subsequently brought into thedesired form. Examples of solid carrier materials include lactose,mannitol, starch, talc, methyl cellulose, silicic acid, calciumphosphate, magnesium stearate, agar-agar and gelatine to which, ifdesired can be added coloring materials and/or flavoring materials.Liquid carriers for injection solutions must be sterile and arepreferably placed into ampoules. They are preferably administered in theform of tablets or dragees with a content of active material of 100-500mg per tablet or dragee. The tablets can thereby contain further solidcarrier materials, for example, starch, lactose, methyl cellulose, talc,highly dispersed silicic acid, high molecular weight fatty acids,magnesium stearate, gelatine, solid high molecular weight polymers (forexample polyethylene glycols) and, if desired, also flavoring and/orcoloring agents.

Suspensions are preferably administered with a content of activematerials of 20-100 mg/ml, using water as the suspension agent. For thestabilization of the suspensions, there can be added high molecularweight, water-soluble materials, for example, cellulose ethers orpolyethylene oxide. Furthermore, there can also be added sweeteningagents, flavoring agents, odiferous materials and/or coloring agents.

For injection solutions, the compounds of general formula (I) arepreferably used in aqueous solution in amounts from 10-100 mg/dosage.Such injection solutions preferably also contain conventional additives,for example, stabilization agents, solubilizing agents, buffers andmannitol or sodium chloride in the amount necessary to produce anisotonic solution.

The active compounds of this invention will be administered to theafflicted subject according to methods known to the skilled artisanafter being formulated as disclosed hereinabove or otherwise as alsoknown in the art. Particularly in the application of the instantcompounds to prevent or combat infections of the urinary tract, dosagesof from 10 to 500 mg/kg of body weight may be desirably used, and thesedosages are conveniently administered three times a day. However,different dosages may be appropriate in a given set of circumstances.

It will be understood that the foregoing specification and examples areillustrative but not limitative of the present invention inasmuch asother embodiments within the spirit and scope of the invention willsuggest themselves to those skilled in the art.

What is claimed is:
 1. Cyclopenteno-quinolone compound of the formula##SPC4##wherein R is saturated or unsaturated aliphatic hydrocarbyl ofup to 5 carbon atoms, X is hydrogen or alkyl of up to 5 carbon atoms, Yis alkylthio or alkylsulfonyl,and the pharmacologically compatible saltsthereof.
 2. Cyclopenteno-quinolone compound as claimed in claim 1,wherein R is alkyl of up to 3 carbon atoms.
 3. Cyclopenteno-quinolonecompound as claimed in claim 1, wherein X is hydrogen. 4.Cyclopenteno-quinolone compound as claimed in claim 1, wherein X isalkyl of up to 3 carbon atoms.
 5. Cyclopenteno-quinolone compound asclaimed in claim 1, wherein Y is alkylthio or alkylsulfonyl of up to 3carbon atoms in the alkyl moiety.
 6. Cyclopenteno-quinolone compound asclaimed in claim 1, wherein said compound is1-ethyl-3-carboxy-1,4-dihydro-7-methylsulphonyl-cyclopenteno [1,2-h]quinol-4-one.
 7. Pharmaceutical composition having bacteriostaticactivity comprising a pharmaceutically acceptable carrier and, ineffective amounts, at least one cyclopenteno-quinolone compound asclaimed in claim
 1. 8. Method of inducing a bacteriostatic effect in asubject which method comprises administering to such subject effectiveamounts of at least one cyclopenteno-quinolone compound as claimed inclaim
 1. 9. Method as claimed in claim 8 wherein such compound isapplied in amounts of from 10 to 500 mg per dosage unit.
 10. Method asclaimed in claim 8 wherein said compound is selectedfrom:1-ethyl-3-carboxy-7-chloro-1,4-dihydrocyclopenteno [1,2-h]quinol-4-one, 1-ethyl-3-carboxy-7-azido-1,4-dihydrocyclopenteno [1,2-h]quinol-4-one,and1-ethyl-3-carboxy-1,4-dihydro-7-methylsulphonyl-cyclopenteno [1,2-h]quinol-4-one.